This invention relates to pulmonary physiology and cardiology.
Nitric oxide (NO) is a highly reactive free radical compound produced by many cells of the body. It relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate (cGMP), leading to vasodilation.
When inhaled, NO gas acts as a selective vasodilator of human and animal pulmonary vessels. Consequently, NO inhalation is used to promote vasodilation in well-ventilated regions of the lung. In acute respiratory distress syndrome (ARDS), impaired ventilation of lung tissue reduces oxygenation of arterial blood. Nitric oxide inhalation often improves oxygenation in ARDS patients. It does so by dilating blood vessels in well-ventilated portions of the lung, redistributing blood flow towards the well-ventilated regions and away from poorly-ventilated regions, which receive little NO. However, in 30-40% of ARDS patients, NO inhalation fails to improve arterial oxygenation (Bigatello et al., 1994, Anesthesiology 80:761-770; Dellinger et al., 1998, Crit. Care Med. 26:15-23). It is difficult to predict which patients with ARDS will not respond to NO inhalation or which patients will respond only transiently. However, it is known that up to 60% of patients with ARDS associated with sepsis do not respond to inhaled NO (Krafft et al., 1996, Chest 109:486-493).
Normal pulmonary vasculature constricts in response to alveolar hypoxia. In patients with lung injury such as ARDS, hypoxic pulmonary vasoconstriction (HPV) raises the level of systemic arterial oxygenation by redistributing blood flow away from a poorly ventilated (hypoxic) lung or lung region toward a well-ventilated (normoxic) lung regions. Sepsis and endotoxemia impair HPV (Hutchinson et al., 1985, J. Appl. Physiol. 58:1463-1468) leading to a profound decrease in arterial oxygen concentrations. Such a decreased level of systemic oxygenation can be life-threatening. Nitric oxide inhalation might be expected to improve oxygenation or arterial blood during sepsis, by increasing blood flow in well-ventilated regions on the lung. In practice, however, NO inhalation during sepsis is often ineffective, and sometimes is deleterious, because of NO inhalation-related reduction of HPV. See, e.g., Gerlach et aL., 1996, xe2x80x9cLow levels of inhaled nitric oxide in acute lung injury,xe2x80x9d pages 271-283 in Nitric Oxide and the Lung, (Zapol and Bloch, eds.), Marcel Dekker Inc, New York.
Endogenous NO is produced by nitric oxide synthases through conversion of L-arginine to L-citrulline in the presence of oxygen (Knowles et al., 1994, Biochemistry 298:249-258). Three different forms of nitric oxide synthase (NOS) have been characterized. Neuronal NOS (NOS1) and endothelial NOS (NOS3) are constitutive enzymes. An inducible NOS known as NOS2 capable of producing large amounts of NO is induced by endotoxin (also referred to as lipopolysaccharide or LPS) and cytokines (Knowles et al., supra). In spite of the demonstrated value of NO inhalation therapy for various indications, impaired pulmonary vascular dilatory responsiveness to NO inhalation and NO-related loss of HPV remain significant problems in acute respiratory illness.
The inventors have discovered that an increased pulmonary NO level is necessary to to impair HPV during sepsis, and that such HPV impairment can be ameliorated by reactive oxygen species scavengers or leukotriene blockers. Accordingly, the inventors have developed methods for preserving the vasodilatory effect of NO inhalation to achieve improved arterial blood oxygenation in patients with lung injury, while ameliorating HPV-reducing effects of NO inhalation. The inventors have discovered that the impairment of HPV is not simply NO-mediated vasodilation. The inventors also have discovered that an elevated level of pulmonary NO plus other lipopolysaccharide-induced agents are necessary to impair pulmonary vasodilatory responsiveness to NO inhalation in endotoxin-challenged mice. Accordingly, the inventors have developed methods for preserving pulmonary vasodilator responsiveness to NO inhalation.
In one aspect, the invention features a method for reducing, partially preventing or completely preventing NO inhalation-related impairment of HPV in a mammal. In one embodiment, the method includes administering to the mammal a therapeutically effective amount of NO by inhalation, and co-administering an effective amount of an anti-reactive oxygen species (anti-ROS) agent. The anti-ROS agent can be, e.g., N-acetylcysteine, allopurinol, ascorbic acid (vitamin C), bilirubin, caffeic acid, catalase, PEG-catalase, ceruloplasm, copper diisopropylsalicylate, deferoxamine mesylate, dimethylurea, ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one; Pz51), EUK-8, FeTMTPyP (5, 10, 15, 20-tetrakis(N-methyl-4xe2x80x2-pyridyl)porphinato iron (III) chloride), FETPPS (5, 10, 15, 20-tetrakis(4-sulfonatophenyl)porphyrinato iron (III) chloride), glucocorticoids, glutathione, MnTBAP (Mn(III)tetrakis(4-benzoic acid)porphyrin chloride), MnTMPyP (Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride), selenomethionine, superoxide dismutase (SOD), polyethylene glycol-conjugated-SOD (PEG-SOD), Taxifolin (dihydroquercetin; 3,3xe2x80x2,4xe2x80x2,5,7-pentahydroxyflavone), and vitamin E. N-acetylcysteine is a preferred anti-ROS agent. In alternative embodiment, the method includes administering a therapeutically effective amount of NO by inhalation, and co-administering an effective amount of a leukotriene blocker. In other embodiments, two or more anti-ROS agents, or an anti-ROS agent and a leukotriene blocker are co-administered with NO inhalation.
In another aspect, the invention features methods for reducing, partially preventing or completely preventing loss of pulmonary vasodilatory responsiveness to NO inhalation in a mammal. In one embodiment, the method includes administering to the mammal a therapeutically effective amount of NO by inhalation, and co-administering an effective amount of an anti-ROS agent. In alternative embodiment, the method includes administering a therapeutically effective amount of NO by inhalation, and co-administering an effective amount of a leukotriene blocker. In other embodiments, two or more anti-ROS agents, or an anti-ROS agent and a leukotriene blocker are co-administered with NO inhalation.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art to which the invention belongs. In case of conflict, the present application, including definitions, will control. All publications, patents, and other documents mentioned herein are incorporated by reference.
Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are described below. The materials, methods and examples are illustrative only and not intended to be limiting. Other features and advantages of the invention will be apparent from the detailed description and from the claims.